Bis-(alkyl sulfonyl and sulfoxyl) aliphatic acid derivatives



- following two equations:

- llnited States Patent Oflice 2,978,480 V Patented Apr. 4, 196 11; ,7

BIS-(ALKYL SULFONYL AND SULFOXYL) ALIPHATIC ACID DERIVATIVES Raymond W. Luckenbaugh, Wilmington, Del., assignor to E. I. du Pont deNemours and Company, Wilmington, Del., a corporation of Delaware No Drawing. Filed May 8, 1957, Ser. No. 657,721

4 'Claims. (Cl. 260-4651) where: R and R are the same or different and are substituted or unsubstituted lower alkyl groups or 'sub stituted or unsubstituted aryl groups, R and R are either hydrogen or substituted or unsubstitutedv lower alkyl groups, Q is either CN or --COOR R is alkyl of 1 to 18 carbon atoms, and x is 1 or 2. 7

.By ?lower alkyl is meant alkyl groups containing less than seven carbon atoms. When such alkyl groups are further substituted, the substituents are hfydrorgyl, halo (preferably ohloro or bromol, nitro, and .cyano. Unless otherwise indicated in this application the word alkyl indicates an unsubstituted saturated aliphatic hydrocarbon radical. 0 By ary is preferablymeant phenyl' and when such aromatic nuclei are substituted, the substituents are hydroxyl, halo (preferably chloro or bromo),nitro and cyano. H I Preferred embodiments ofthe present invention are those compoundswithin the scope of Formula l, aboye where R R R R and Q have the same significance as in Formula 1 and hal represents halogen.

The sodio bis-(alkyl or aryl sulfonyl) methanes used as starting materials for the above-indicated process can be made in accordance with the procedure described by M. W. Cronyn, I. Am. Chem. Soc. 74, 1228-9 (1952). In brief, this procedure comprises adding, say, 0.625 mole of a bis-(alkyl or aryl sulfonyl) methane to a solution of 14.4 g. (0.625 mole) of sodium dissolved in 200 cc. of warm absolute ethanol. The resulting mixture is swirled and warmed for a few" minutes to give a clear solution. The solution is cooled rapidly to room temperature and dry ether (200-250 cc.) is 'addedin when R and R are the same and are substitutedor u b t edja k l i to 3- a o a R3"a d R4 are the same and are' hydrogen, methyl or ethyL Q is COOR or -CN, R is alkyl of l to 1 8 carbonatoms,

andxis2. p V The. bis-(sulfonyl and sulfoxyl) substituted; alkyl carboxylic acid esters and allgyl Vnitrile derivatives repre sented by Formula 1 can be made by various methods. One method which is very satisfactory consists inreacting appropriate halides with.bise(all ylsulfonyl) -meth-.

This preparative V anes or bis-(alkylsulfoxyl) methanes.

method can be more fullyunderstood by reference to the mso. 'Riso,

product obtained as in method first'described above in an oil-bath. When the internal temperature has'rise portions with swirling until a faint cloudiness appears. The ether should not be used to force the product from solution or it will be amorphous and hygroscopic. If the salt does not immediately crystallize, the mixture is warmed momentarily. The mixture is then cooled in air, filtered, and the precipitate collected, and washed with 1 1 alcohol-ether to 'give about a yield of the sodio bis-(alkyl or aryl sulfonyl) methane. The resulting compound is stable as long as it is protected from carbondioxide and moisture; Exposure'to air, however, does not noticeably change the appearance of the salt.

The sodio salt of the disulfone (or disulfoxide) can be monoalkylated with an appropriate halide by a variety of methods. In one method molecular equilav'ents of the sodio salt and the halide is thoroughly mixed in a volume of dimethylformamide which is generallyjllS to 2 times the weight of thesodio salt. The time required to reach a nearly neutral solution is about 30 minutes at 80-90 C. fora bromide and an hour at -1291 C. 1 for a. normalchlor ide. These times are preferably doubled. The solution is stirred. The reactionniixtiire i's then-diluted with water. 1 Usually the 'product crys- '11 tallizes upon cooling and is collected by'filtra'tibn. if the product remains an oil, it can be extracted with ether, dried, and concentrated. Crystallization can be induced with petroleum ether. l e The sodio salt can also be 'Imade in the dimethyl j for-mamide by adding the bis-(alkylsulfonyl)-metliane to A heating. A n

Still another' monoalkylation methodcomprises ingpotassium fhydr'oxide in'ten times its fweiglit 9 ethyl ca'rbitol-l' The solution is" stirred during fcoolin The disulfone is 'addedand the mixture stirred-andhefe'd to ;C., and most o'f the'water has been removed byg distillation, the'biomide is added and the stirringi and" heating iscontimiedgih an oil-bath maintained-150 C. for an hour or until-the solution'is neutral A fourth method or monoalkylating the sodiolsa involves refluxing, equivalent'amo'unts. of thesod of f the disulfpne and the brOmideJin-abscrlute etlia'n 36 to -'48 hou'rs.. Ihe alcohol is thenreniovedfafid he The bis-sulfones and sulfoxides used to prepare the sodio bis-(alkyl or aryl s'ulfonyl) methanes can be made by any of the following methods:

1) Method described by M. W. Cronyn, I. Am. Chem. Soc. 74, 1228 (1952).

(2) Method of preparation of'mixed sulfoxides and sulfone.

lHnOI RSOgCHzSOR' An alternative route to the bis-(alkyl sulfonyl and sulfoxyl) aliphatic acid derivatives of Formula 1 involves the oxidation of an appropriate disulfide which can be prepared by condensation of a mercaptan with aldehydes. This route can be illustrated by the following equations:

NaOEt H 0 CzHs-l-CHa-CO ORr-1H(Il=CHC 0 OR;

ONa

wherein R and R have the same significance as in Formula 1. It will be understood that any of a wide variety of oxidizing agents common to the art for oxidizing sulfides to sulfones and sulfoxides can be used. For example, there may be used hydrogen peroxide, peracetic acid, potassium permanganate and the like.

Still another alternative method for preparing the compounds of Formula 1 involves the addition of two molecules of a mercaptan to the triple bond of a propiolic acid ester, followed by oxidation. This reaction can be illustrated by the following general equations:

wherein R and R have the same significance as in Formula 1. A suitable method for the preparation of the compounds of Formula 1 where Q is a nitrile groupconsisting in reacting a sodio bis-(alkyl or aryl sulfoxyl) methane with a halo acetonitrile, e.g. bromo acetonitrile. Alternatively, the sodio saltmay be reacted with a halo acetamide, eg. Z-bromo-acetamide; The formed propionamide derivative may then be converted to the corresponding nitrile by means of dehydrating agents such as phosphorus pentoxide or thionyl chloride. p j p The. bis-(alkyl sulfonyl and sulfoxyl) aliphatic acid derivatives of Formula 1 are useful as pesticidical agents, especially asantifungal agents, and-as bactericidal, and protozoicidalagents. They are of particular value because of the wide spectrum of in vitro activity. they possess against bacteria, fungi,.protozoa, and algae at low concentration (less than 50 p.p.m.). V a 5 a In; practicing the fungicidal methods of;my invention,

4 a bis-(alkylsulfonyl'or sulfoxyl) aliphatic acid derivative of the invention is applied to the material to be treated for the control of fungi at a dosage sufficient to exert fungicidal action. Accordingly, my compounds can be used, for example, to treat living plants such as vegetables, ornamental plants, and fruit-bearing trees. Also they may be used to treat organic fibers or fabrics and various cellulosic materials such as paper, cardboard and wood. Likewise, they may be used to treat paints and lubricating oils. One important utility appears to be in the control of fungus diseasm of agricultural crops or ornamental lants.

p The dosage employed in the fungicidal methods of the invention is largely determined by and dependent upon the particular fungicidal compound selected, and, in the case of application to vegetation, the susceptibility of the particular vegetation to the compound selected, the state and condition of growth of the vegetation to be treated, and the climatic conditions.

In general, the fungicidal compositions of my invention contain in sufficient amount to exert fungicidal action a compound of Formula 1 as an active ingredient in admixture with a carrier material or conditioning agent of the kind used and commonly referred to in the art as a fungicide (or pest control) adjuvant. Usually from about 1% to 95% by weight of the fungicidal composition is active ingredient.

The conventional fungicide adjuvants are inert solids, organic liquid diluents and surface-active agents. They provide formulations adapted for ready and efficient application using conventional applicator equipment. Thus, one or more of my fungicidallyactive compounds is admixed with a fungicide adjuvant material to provide a formulation in liquid or solid form.

Solid compositions are preferably in the form of powders. They are compounded to be homogeneous powders that either can be used as such, dilutedwith inert solids to form dusts or suspended in a suitable liquid medium for spray application. The powders can comprise principally the active ingredient and minor amounts of conditioning agent. They can also be prepared by admixing the active compound with large, amounts of finely divided inert solids. Natural clays, either absorptive such as attapulgite or relatively non-absorptive such as china clays, diatomaceous earth, walnut shell flour, redwood flour, synthetic fine silica, calcium silicate and other inert solid carriers of the kind, conventionally employed inwettable powder fungicidal compositions can be used. The active ingredient usually makes up from about 25 to 90% of these wettable powder compositions.

Suitable diluents for. conversion to dusts are talc, pyrophyllite, tobacco dust, volcanic ash and other dense rapid settling inert solids.

Liquid compositions employingone or more of the fungicidal compounds of my invention are prepared by admixing the active ingredient with a suitable liquid diluent media. The active ingredient can be either in so lution or in suspension in the liquid media. I Typical of the liquid media commonly employed as fungicide adjuvants are water, kerosene, Stoddard solvent, xylene, alcohols, alkylatednaphthalene, and glycols. The active ingredient usually makes up'from about 0.5 to 50% ofthese liquid compositions. Some of these compositions are designed to be used as such, others to be extended with large quantities of water.

Compositions in the 'f ormj' of wettable powders or liquids in many cases also include a surface-active agent of the kind sometimes referred to in the art as a wetting, dispersing or emulsifying agent. These materials oxides, lignin sulfonates, and other surface-active agents. A detailed list of such agents is set forth in articles by McCutcheon in Soap and Sanitary Chemicals, August, September and October of 1949.

3,3-bis(ethylsulfonyl)propionic acid, ethyl ester, one

of the preferred compounds of the invention, has been found to give a 100% kill of Candida albicans at levels of 100 p.p.m. and 20 p.p.m. within minutes.

Against. Glomrella cingulata, the compound at 100 p.p.m. produced a 90% or greater kill in 10 minutes and a 100% kill in less than 5 hours; at p.p.m. it produced a 90% kill in 1 hour and over a 99.9% kill in 5 hours. Against Bacillus anthracis and Proteus valgaris 3,3-bis(ethylsulf0nyl)propionic acid, ethyl ester, at 100 p.p.m. caused a 90% or greater kill in one hour and a 100% kill within 5 hours and at 20 p.p.m. it produced a 90% kill in 5 hours.

- In order that the invention may be better understood,

the following specific illustrative. examples are given in addition to those already above indicated.

EXAMPLE I. PREPARATION OF 3,-3-BIS(ETHYL- SULFONYL)PROPIONIC ACID, ETHYL ESTER To a mixture consisting of 60 grams of dimethylformamide and 33.2 grams (0.15 mole) of sodio bis- Minimum- Inhibitor Concentrat on, gamma/ml.

Organism Twenty parts of the 3,3-bis(ethlsulfonyl)-propionic acid, ethyl ester, produced as above-described, is mixed with parts coumarone indene resin, 45 parts ethanol, and 5 parts of an alkyl, aryl polyether alcohol to give a. homogeneous solution. This composition whenemulsi fied in water gives a formulation suitable for application A as a foliar fungicide, particularly against a 7 (-ethylsulfonyl)rnethane there was added 25 grams of 1 ethyl bromoacetate. The mixture was stirred. Its temperature rose rapidly from 24 C. to 84 C. The pI -I Ehytophthora infesrans ofth'e reaction mixture changed from 10106. As the temperature of the solution dropped, steam heat was applied to it to insure completion of the'reaction. The solution was cooled and an equal volume of water added 9 to it. The diluted solution was steam-distilled to remove any unreacted halide. The desired product crystallized and was collected by filtration (M.P. 54.5- 57.5 Upon recrystallization from ethanol, the melting point of the purified product Was found to be 67.5 68.5 C.

Analysis.-Calcd. for C H O S: S, 22.4. Found: S, 22.57; 22.69.

A repeat preparation analyzed as follows:

Calcd. 0, 3.7.8; H, 6.3; s, 22.4. 'Found: c, 37.17, 37.4; H, 6.27, 6.43; S, 22.14, 21.62, 21.56.

In a standardized tube dilution test, 3,3-bis-(ethylsu1fonyl)propionic acid, ethyl ester, ha's the following antimicrobial spectrum:

Minimum Organism' Inhibitory Concentration,

gamma/ml.

Bacteria:

Aerobacter aeroge'nes 25 BaClZZ'LLS anthrac1s 12 Baczllas subtzlzs. 25 Brucella abortus 3 Corynebaclerz'um boat's 25 Di p 25 Escherichia coli 25 Klebsiella A..- e j 12 Micrococcus pyogmes var. aareas 25 Mycobactcrium tabarculosisbooiaen 25 Mycobacteriam phleii 3 Neisseria catarrhalz's 3 Pastearella maltocida. 25 Proteus aalgaris 12 Pseudomonas aeraginosm 50 Salmonella galliaarum 25 Salmonella paratyphi; 25 Salmonella pullorum. Salmonella typhimurium 25 Sarcjnalutea 3 Shiaella iae 12 Streptococcus agalactiae I o r a V n Virbrz'o comma 12 Protozoa:

Strigo'monas culz'cidaram u 2 Tetrahymena pyriformis var. geleiz' 2 Algae: 4

Eaglena graciZz's-Incubated in light j 40 F Poteriochromonas stlpitata -Incubated in light a 2 ungr:

Candida alblcans. 2 Mycoderma lipolytic 25 Rhodotorula sp 12 Saccharcmyces cereazszae 15 Cercospora ap'ii Diplocarpon rosae Botrytis paeoniae Plasmopara viticola EXAMPLE 2.-PREPARATION OF 3,3-BIS(E'IHYL- SULFONYL) PROPIONITRILE Alternaria sola'ni Venturia inaequalis Uromyces appendiculatus To a'slurry of 13.6 grams (0.1 mole). of alpha.-

bromoacetamide in 5 milliliters of dimethylformamide is added a solution of 22.2 grams (0.1 mole) of sodio bis (ethylsulfonyl) methane in 45 milliliters of dimethylformamide in athin stream, while' stirring. I Thete'mperature of the reaction mixture rises rapidly from 25 Y. to 86, then drops. A The temperature'is kept at 70-75" by means of externalheating for a'periodbf 30 minutes.

The pH of the mixture drops to 6.5 during this period.

The reaction mixturejsutaken. up inhot absolute ethanol and filtered to removesodium bromide. The fiiltrate oncooling gives 10.2 grams of white crystals, melting point 165. Recrystallization from absolute ethanol gave 7.5 grams of 3,3- bis(ethylsulfonyl) propionarnide, melting point 168-169.5.

Analysis.Calcd. for C7H15O5NS2Z C, 32.7; H, 5.8; N, 5.4; S, 25.0. Foundi C, 32.98; H, 5.85; N, 542; S, 24.73. I e e This amide is converted to 3,3-bis(ethylsulfonyl) propionitrile in the following manner:

Two grams (0.078 mole) of .3,3-bis(ethylsulfonyl) propionamide are heated to reflux with 10 milliliters of thionyl chloride for a' period of 10 hours. The mixture is vacuum concentrated to an oil, whichicrystallizes upon cooling in ice. The oily crystals are washed with cold absolute ethanol and. subsequently recrystallized from absolute ethanolimtila-contant melting point of 102.5-

103.5 is reached. The white crystalline product weights one gram.

Analysia-Cilddf for C H 3O NS N, 5.8; S, 26.8. Found: N, 5.55; S, 26.97.

7 EXAMPLE 3- 21 r Using the method of Example 1, thatis, the reaction of halides with bis-(alkyl or aryl sulfonyl or sulfoxyl) methanes as earlier described in this specification, there are prepared the compounds of Table 1. The reactants, the amount of each employed, and the structural formula of the resulting product are set forth in this table. The examples of Table 1 are based on 0.1 mole of bis-sulfone and 0.1 mole of halide. A total of 2.3 g. of sodium in 40 m1. ethanol is used in preparation of the sodium salt (sodium hydride (2.4 g.) in dimethylformamide may also be used as already described). 1

Ingredient:

Bis-(3,3-ethylsulfonyl)propionic acid ethyl ester 25 Coumarone indene resin 25 'Alkyl, aryl polyether alcohol (Triton'X-155, commercially available from Rohm & Hass Co.)

Ethanol l 45 This composition can be emulsified in water and when mixed with water is especially suitable as a foliar spray for application by conventional spray equipment for the protection of living plants from fungi attack.

A suspension of containing 0.2% of bis-(3,3-ethylsulfonyl)propionic acid, ethyl ester, is sprayed on to- -mato foliage. After the deposit has dried, the foliage is inoculated with a suspension of spores of the early blight fungus (Alternaria solani) and the foliage is then placed in a chamber where conditions of temperature and humidity suitable for optimum infection are maintained. When suflicient time has elapsed for the formation of visible lesions the foliage is examined. It is found that the treated foliage has 2% disease compared to 100% on the non-treated.

A similar composition containing the active chemical at a concentration of 0.008% is applied to apple foliage. The foliage is inoculated with spores of apple scab fungus (Venturia inaequalis) and placed in a chamber where conditions of temperature and humidity suitable for optimum infection was maintained. The treated foliage has 7% disease compared to 100% for non-treated.

In place of bis-(3,3-ethylsulfonyl)propionic acid, ethyl ester, there can be used in the above formulation any of the ester-type compounds shown above. For example, the compound bis(3,3-methylsulfonyl)propionic acid, ethyl ester, can be employed in place of the compound of Example 1 in the above composition. Such a composition when mixed with water, in an amount such that the aqueous formulation contains 0.2% the propionic acid derivative is sprayed on bean foliage. After the deposit has dried, the foliage is inoculated with a suspension of spores of bean rust fungus (Uromyces appendiculams) and placed in a chamber where conditions of temperature and humidity suitable for optimum infection are maintained. After sufiicient time has elapsed for the formation of visible lesions, the foliage is examined. It is found that the treated foliage has substantially less disease than the untreated.

EXAMPLE 23 A suitable wettable powder of the following composition is blended, micropulverized and reblended.

The resultant wettable powder is suitable for application as an agricultural fungicide. An aqueous suspension of the powder having the active ingredient present at a concentration level of 0.2% is applied to tomato foliage. The foliage is later inoculated with spores of late blight fungus (Phytophthora infestans) and placed in a chamber where conditions of temperature and humidity suitable for optimum infection are maintained. After sufiicient time has elapsed for the formation of visible lesions, the foliage is examined. It is found that the treated foliage has substantially less disease than the non-treated.

Also, in place of the phenyl sulfonyl derivative in the composition of this example, one can use any ester or nitrile falling within the scope of formula 1. Thus, for example, the compound 3,3-bis(ethylsulfonyl)propionitrile can be employed as the active ingredient in a composition of this example to elfectively causing black spot of rose (Diplocarpon rosae).

EXAMPLE 24 7 A suitable wettable powder of the following composition is prepared by mixing the ingredients and passing the mixture thru a micropulverizer:

Bis-.(3,3-ethylsulfonyl)propionic .acid, 11. butyl ester 50 Synthetic calcium silicate (micro-eel) 49.25 Low viscosity methyl cellulose 0.25 Alkylated naphthalene sodium sulfonate (commercial wetting agent) 0.50

When made into an aqueous suspension by the addition of water, this suspension is suitable for a foliar spray. A suspension containing 0.2% of the propionic acid derivative is sprayed on peony foliage. After the deposit has dried, the foliage is inoculated with a suspension of spores of Botrytis paeoniae. The foliage is then placed in a chamber where temperature and humidity suitable for optimum infection are maintained. When sufficient time has elapsed for the formation of visible lesions, the foliage is examined. It is found that the treated foliage has substantially less disease than non-treated.

In place of the propionic acid derivative of the above composition, octyl ester of Example 7 can be employed in an equal amount by weight to prepare a suitable wettable powder. Such a powder wets readily and forms a good dispersion when mixed with a large quantity of water. Such a dispersion is effective in controlling the downy mildew of grapes caused by Plasmopara viticola.

EXAMPLE 25 A free-flowing dust is prepared by blending 50 parts of 3,3 bis (methylsulfonyDpropionic acid,

methyl ester, and r 50 parts of kaolin clay and passing the resulting blend through a micropulverizer.

This application is a continuation-impart of US. appli cation Serial No. 583,895, .filed May 10, 1956, now abandoned.

The claims are: 1. A compound characterized by the formula H o- -oN Rz-SO; R4

where: R and R are selected from the group consisting of hydroxy lower alkyl, halo lower alkyl, nitro lower alkyl, cyano lower alkyl, lower alkyl, nitrophenyl, chloro- I phenyl, and phenyl; R and R are selected from the group consisting of hydrogen, hydroxy lower alkyl, halo lower alkyl, nitro lower alkyl, cyano lower alkyl, and lower alkyl; and x is a positive whole number less than 3. t

2. A compound characterized by the formula where: R and R are selected from the group consisting of hydroxy lower alkyl, halo lower alkyl, nitro lower alkyl, cyano lower-alkyl, lower alkyl, nitrophenyl, chlorophenyl, and phenyl; R and R are selected from the A group consisting of hydrogen, hydroxy lower alkyl, halo lower alkyl, nitro lower alkyl, cyano lower alkyl and tartar a... was

11 lower alkyl; R is an alkyl radical containing from 1 through 18 carbon atoms; and, x is a positive Whole number'less than 3.

3. Bis-(3,3-ethy1sulf0nyl) propionic acid, ethyl ater. 4. Bis-(3,3-ethylsulfonyl) propiom'trile.

References Cited in the file of this patent UNITED STATES PATENTS 12 Gresham Oct. 26, 1948 Denton Feb. 7, 1950 Skinner et a1. June 19, 1951 Buckmann Nov. 18, 1952 OTHER REFERENCES Rothstein: J. Chem. Soc. (London), December 1940,

pages 1560-1565.

Bohme et aL: Chem. Abstracts, vol. 40, pages 2809- De Groote et a1 Jan. 7, 1947 10 2811 (1944). 

1. A COMPOUND CHARACTERIZED BY THE FORMULA 